Elevated pulse pressure preceded incident chronic kidney disease in the general older population in Sweden

Arterial stiffness (AS) and chronic kidney disease (CKD) are common in the older population. AS results in increased pulsatile pressure, elevated pulse pressure (PP), and is linked to hypertension. PP is a surrogate for AS. The kidney has low vascular resistance mechanisms, presumably making it vulnerable to the increased pulsatile pressure and hypertension associated with AS. The aims of this study were to investigate the impact of PP elevation on incident CKD (glomerular filtration rate < 60 ml/min/1.73 m2) and all-cause mortality. The data was collected from the general population cohort study “Good Aging in Skåne”. Cox proportional hazard regression models adjusted for age, sex, diabetes, and smoking habits were used to investigate the impact of three levels of PP elevation on incident CKD (n = 2693) and all-cause mortality (n = 5253). For PP < 60 mmHg, the median survival time was 18.7 years (event incident CKD) and first quartile survival time (event all-cause mortality) 15.4 years. Elevated PP ≥ 80 mmHg was associated with incident CKD (hazard ratio 1.59, CI 1.28–1.97), but not all-cause mortality. Our results suggest that a finding of PP ≥ 80 mmHg in older age should raise concern of kidney function.


Participants at inclusion n=5804
Participants left in the study n=2693

No visits following the inclusion visit in GÅS n=1451
Missing blood samples, PP, BMI or missing data regarding diabetes or smoking habits n=485

CKD at inclusion n=951
Missing blood samples or missing BMI at all visits following the inclusion visit n=224 www.nature.com/scientificreports/

Pulse pressure
Blood pressure (BP) was assessed by a physician using a sphygmomanometer.BP was measured in a sitting position in the left arm after a 5-min rest using an appropriately sized cuff (standard 12 cm, smaller 9 cm, or a wider 15 cm).PP was assessed by subtracting the DBP from the SBP.The European Society of Cardiology (ESC) defines having a PP ≥ 60 mmHg as presence of AS in older people 21 .Franklin et al. also found that an elevated PP around this level was associated with future cardiovascular events in the Framingham study 22 .Myers et al. 23 however, found an association between PP and cardiovascular events first when PP was > 80 mmHg.In line with the ESC, elevated PP was defined as PP ≥ 60 mmHg, and normal PP was defined as < 60 mmHg.Associations between three levels of elevated PP and incident CKD and/or all-cause mortality were examined: 60-< 70 mmHg, 70-< 80 mmHg, and ≥ 80 mmHg.

Mortality
The date of death was obtained by linkage to the Swedish people and address register from the date of the baseline visit until September 9, 2020.Thus, all individuals were followed up for mortality, regarding additional participation in the GÅS study until emigration or death, whichever occurred first.

Other covariates
To control for potential confounders masking the hypothetical association between elevated levels of PP and CKD and/or death, the traditional cardiovascular risk factors age, sex, diabetes, and smoking habits were assessed at baseline, and included as covariates in the statistical models 1,9 .HT is heavily linked to AS and PP 6,12 .To avoid collinearity, HT was not included as a covariate.
Diabetes was defined as having diabetes mellitus type 1 or 2 at baseline.A history of diabetes was assessed by a physician through interview and by review of the medical records.
Smoking was self-reported and defined as either active or former smoker, or never smoked.Smoking status was assessed at baseline.
BMI was assessed at baseline.Weight and height were measured by a nurse.The following formula was used to assess BMI: Weight (kg)/Height (m) 2 .
Cohort was defined as have been recruited to the GÅS study between 2001 and 2004, between 2006 and 2012, and between 2012 and 2016.

Statistics
Cox proportional hazard regression models were used to investigate the association between the exposure of three different levels of elevated PP (60-< 70 mmHg, 70-< 80 mmHg, and ≥ 80 mmHg) compared to normal PP (< 60 mmHg) at the baseline visit and the event of incident CKD (eGFR < 60 ml/min/1.73m 2 ) during the follow-up period.Each subject contributed to the analysis from the baseline visit until the event or the last GÅS visit, whichever occurred first.Cox proportional hazard regression models were used to calculate the hazard ratio (HR) for CKD for the different levels of PP elevation compared to normal PP at baseline.The models were first set up unadjusted, and thereafter adjusted for age, sex, diabetes, smoking habits, BMI and cohorts.
In a secondary analysis, the association between elevated PP, set at 60-< 70 mmHg, 70-< 80 mmHg, and ≥ 80 mmHg (< 60 mmHg as reference), at the baseline visit and all-cause mortality was investigated using Cox proportional hazard regression models, both unadjusted and adjusted for the same covariates as above.
To estimate the median and first quartile survival time from the baseline visit until the events, Kaplan-Meier analyzes were used.All three levels of PP elevation mentioned above was examined compared to normal PP, both when the event was incident CKD, and all-cause mortality.
All statistical analyzes were performed using the IBM SPSS software version 29.

Participants at inclusion n=5804
Participants left in the study n=5253

Ethical considerations
The study was approved by the Ethics Committee of Lund University, Sweden (reference number: LU 744-20) and was conducted in accordance with the Declaration of Helsinki.The Division of Geriatric Medicine at Lund University granted and gave permission to access and use the raw data in the study.All subjects or informants gave their written informed consent.

Results
The baseline characteristics of the participants are shown in Tables 1 and 2.

Elevated pulse pressure and incident chronic kidney disease
Participants with elevated PP at the baseline visit more often developed CKD (eGFR < 60 ml/min/1.73m 2 ) during the follow-up period compared to those with normal PP (< 60 mmHg).The CKD incidence increased at higher levels of PP elevation.The CKD incidence during the follow-up period increased from 28.5% for those with PP 60-< 70 mmHg at the baseline visit to 50.8% for those with PP ≥ 80 mmHg.This is demonstrated in Table 1.
In an unadjusted model, all levels of PP elevation at the baseline visit were associated with incident CKD during the follow-up period, and the HR increased at higher levels of PP elevation.Unadjusted, the HR for developing CKD was 1.68 (CI 1.39-2.04,p-value < 0.001) for participants with PP 60-< 70 mmHg compared to those with PP < 60 mmHg at baseline.For subjects with PP ≥ 80 mmHg, the HR for incident CKD was 3.37 (CI 2.77-4.10,p-value < 0.001).This is demonstrated in Table 3.
After adjustments for covariates, the association between PP ≥ 80 mmHg at baseline and incident CKD during the follow-up period remained.For PP ≥ 80 mmHg, the HR was 1.59 (CI 1.28-1.97,p-value < 0.001), as listed in Table 3.

Elevated pulse pressure and all-cause mortality
In an unadjusted model, associations were seen between all levels of PP elevation and all-cause mortality, and the HR increased at higher levels of PP elevation.Unadjusted, the HR for all-cause mortality was 1.63 (CI 1.42-1.88,p-value < 0.001) for participants with PP 60-< 70 mmHg (compared to those with PP < 60 mmHg) at the baseline visit.For subjects with PP ≥ 80 mmHg, the HR was 3.50 (CI 3.10-3.96,p-value < 0.001).This is demonstrated in Table 4.
After adjustments for covariates, no associations between any level of PP elevation at the baseline visit and all-cause mortality during follow-up remained, as listed in Table 4.
When all-cause mortality was the event, the median survival time could not be calculated for the reference group (PP < 60 mmHg) and the group with PP 60-< 70 mmHg.Hence, the first quartile survival time was calculated instead.The time in years for survival of the first quartile was 12.0 (95% CI 11.0-12.8)for the group with PP 60-< 70 mmHg, 10.9 (95% CI 9.7-12.3),for the group with PP 70-< 80 mmHg, and 6.8 (95% CI 6.0-7.4) for the group with PP ≥ 80 mmHg, compared to 15.4 (95% CI 14.3-16.2) for the group with normal PP (< 60 mmHg).A survival plot is demonstrated in Fig. 4.

Discussion
In this study we investigated the impact of PP elevation at three levels (60-< 70 mmHg, 70-< 80 mmHg, and PP ≥ 80 mmHg) on incident CKD and all-cause mortality in a general population cohort of older adults.Elevated PP ≥ 80 mmHg was associated with incident CKD.No level of elevated PP was associated with all-cause mortality.Our findings suggest that PP elevation ≥ 80 mmHg is associated with incident CKD in the general older population.
A sensitivity analysis was made where the statistical model for the impact of elevated PP on incident CKD including the same covariates was re-run with GFR estimated using the CKD-EPI equation based on crea/cysC in all participants.The number of subjects included was 2731.The association remained.The 95% CI for PP 60-< 70 mmHg was 0.98-1.46,p-value 0.082.The 95% CI for PP 70-< 80 mmHg was 0.78-1.27,p-value 0.963.The 95% CI for PP ≥ 80 mmHg was 1.26-1.96,p-value < 0.001.
Analyzes from the Health ABC study (n = 2129), as well as analyzes from the Rotterdam study (n = 3666), showed that AS was associated with incident CKD 24,25 .Analyzes from the Framingham Heart Offspring cohort (n = 1675) however, found no association between AS and incident CKD 26 .The results from these three studies cannot be fully compared to the results of this study.Even though all three studies defined CKD as eGFR < 60 ml/ min/1.73m 2 , they estimated GFR from either cysC or crea, not from crea/cysC, which entails a risk of misclassification regarding CKD status in the non-underweight population.The first two studies did measure PP as a surrogate for AS, but neither one of them investigated the impact of different levels of elevated PP on incident CKD.The last study measured PWV to assess AS, not PP.
Although we did not observe an association between elevated PP and all-cause mortality in this study, it is possible that an association in fact does exist.Most previous longitudinal studies investigating the impact of elevated PP on mortality have indeed found that elevated PP is associated with mortality, as presented in a large review (n = 510,456) on the subject from 2014 14 .The time required to develop CKD is most likely far less than the time required to die.It is possible that the sample size was too small to detect an association between elevated PP and all-cause mortality.
Table 1.Characteristics of the study sample (outcome incident CKD).CKD defined as eGFR < 60 ml/ min/1.73m 2 . 1 eGFR in ml/min/1.73m 2 . 2 Hypertension defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 and/or current pharmacological treatment for hypertension.Current pharmacological treatment of hypertension was defined as being treated with any of the following classes of pharmaceuticals with hypertension as indication (Anatomical Therapeutic Chemical codes (ATC) in parenthesis): Antihypertensive agents (ATC02), Diuretics (TC03), Beta-blockers (ATC07), Calcium antagonists (ATC08), RAS inhibitors (ATC09). 3SBP in mmHg taken in a sitting position in the left arm after a 5-min rest. 4DBP in mmHg taken in a sitting position in the left arm after a 5-min rest. 5Diabetes defined as type 1 or type 2 diabetes. 6Smoking defined as active or former smoker. 7BMI = Weight (kg)/Height (m) 2 . 8Coronary insufficiency defined as history of AMI, PTCA, CABG, or angina pectoris. 9Stroke defined as history of cerebral infarction, TIA, or RIND.AHI, acute myocardial ischemia; ATC, anatomical therapeutic chemical codes; BMI, body mass index; CABG, coronary artery bypass graft surgery; CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, Estimated glomerular filtration rate; Kg, kilograms; M, meters; PP, pulse pressure; PTCA, percutanous transluminal coronary angioplasty; RIND, reversible ischemic neurological deficit; SBP, systolic blood pressure; SD, standard deviation; TIA, transient ischemic attack.Table 2. Characteristics of the study sample (outcome all-cause mortality).CKD defined as eGFR < 60 ml/ min/1.73m 2 . 1 Hypertension defined as SBP ≥ 140 mmHg and/or DBP ≥ 90 and/or current pharmacological treatment for hypertension.Current pharmacological treatment of hypertension was defined as being treated with any of the following classes of pharmaceuticals with hypertension as indication (Anatomical Therapeutic Chemical codes in parenthesis): Antihypertensive agents (ATC02), Diuretics (TC03), Betablockers (ATC07), Calcium antagonists (ATC08), RAS inhibitors (ATC09). 2 SBP in mmHg taken in a sitting position in the left arm after a 5-min rest. 3DBP in mmHg taken in a sitting position in the left arm after a 5-min rest. 4Diabetes defined as type 1 or type 2 diabetes. 5Smoking defined as active or former smoker. 6BMI = Weight (kg)/Height (m) 2 . 7Coronary insufficiency defined as history of AMI, PTCA, CABG, or angina pectoris. 8    Elevated PP is the result of a large discrepancy between SBP and DBP.However, low DBP itself has been proposed as a risk factor for increased mortality and adverse effects like cardiovascular events, dementia, stroke, and reduced renal function [27][28][29][30][31] .Adverse associations seem to be especially true in the elder population 30 .The increased risk of low DBP can be attributed to reduced organ perfusion but also reversed causation like comorbidities or frailty.In the non-acute setting, low DBP has been associated with AS, excessive anti-hypertensive treatment, heart failure, autonomic dysfunction and hemodynamic properties like low blood volume or exaggerated venous pooling 30,32,33 .To examine if the impact of elevated PP on incident CKD and on all-cause mortality remained independent of DBP, the statistical models were re-run with adjustments made for the same covariates as before but also with DBP included.The results remained essentially the same.The results are presented in Supplementary Tables S1 and S2.
Impairment of the elastic properties of the large arteries due to loss of elastin, fibrosis, and calcification of the arterial vessel walls results in AS, which progresses with age and is very common in the older population 11 .HT is strongly associated with AS 6 .If HT is a cause of AS or vice versa is debated 34 .AS causes reduced compliance in the large arteries.This results in elevated PWV and increased pulsatile pressure, which is insufficiently dampened by the resistance arteries, leading to increased stress to the microcirculation of end organs 6 .The kidney and the brain are high energy consuming organs and depend on a stable and continuous blood flow.The microvasculature of the kidney and the brain are likely highly sensitive to the increased PWV and pulsatile pressure accompanying AS, since both the kidney and the brain have low vascular resistance properties compared to other organs 5 .
CKD is heavily linked to cardiovascular disease, but if CKD is a result of vascular damage or vice versa (or both) is less known 35 .The kidney is likely sensitive to vascular damage for reasons described above.Since this was an observational study, even though AS preceded CKD, it is difficult to make any causal assumptions.A theory is that AS could be a contributing cause of CKD, at least initially in the pathological process.CKD can most likely in turn induce vascular damage through increased inflammation and uremic toxins 36 , and as CKD and vascular damage worsen, cause and effect are likely to become increasingly difficult to establish.
Elevated PP is a surrogate for AS 10 .PP can be assessed easily by simply subtracting the DBP from the SBP measured in rest.The only instruments needed are a blood pressure cuff and a stethoscope, which are usually included in the standard equipment of a standard clinical practice.In this study, PP ≥ 80 mmHg was associated with incident CKD in the general older population.PP elevation is common in the older population 8 , and has previously been shown to increase the risk of cardiovascular events beyond the risk posed by HT alone 9 .A finding of PP ≥ 80 mmHg should raise concern regarding kidney function and possibly the cardiovascular status of the older patient.We recommend assessment of kidney function through estimation of GFR in case of a finding of PP ≥ 80 mmHg.In case of a finding of PP ≥ 80 mmHg, we also suggest that evaluation and management of traditional, treatable cardiovascular risk factors, such as hypertension, diabetes, and smoking habits are considered.
A strength of this study includes the large number of participants representing the general older population, as well as the long follow-up period.Another strength is that GFR was estimated from both crea and cysC in the non-underweight, and that consideration was taken to possible misclassification in the underweight by only estimating GFR from cysC in this group.Furthermore, using the established cut-off limit of eGFR < 60 ml/ min/1.73m 2 to define CKD enables to study mechanisms of early signs of CKD in the general older population.Another strength was the use of three levels of PP elevation.
This study had some limitations.Since almost all subjects with elevated PP (≥ 60 mmHg) also had HT (89.2%), no stratification could be made based upon HT status.Therefore, this study could not determine if elevated PP is associated with incident CKD or all-cause mortality independent of HT.Since we had no data regarding the cause of death of the subjects who died during follow-up, we could not determine if PP elevation was associated with cardiovascular mortality.Microalbuminuria was not measured during the study, which may have resulted in underestimation of true association due to a dilution effect, as the eGFR limit < 60 ml/min/1.73m 2 may be part of normal ageing.The invitation interval was longer for participants who were younger than 78 years of age.Therefore, changes in their kidney function were detected every 6 years.By study design, any decline in kidney function before that time is noted later for younger participants.Chronic kidney disease is a complex disease with several risk factors, such as age, sex, diabetes, hypertension, obesity, environmental factors, etc 37 .Despite the inclusion of the main risk factors in the statistical models, residual confounding remains and therefore the results presented in this work should be interpreted with caution.According to protocol, participants with SBP ≥ 140 mmHg and/or DBP ≥ 90 at the baseline visits were recommended follow-up for hypertension at their general practitioner's office.As this procedure constitutes an intervention, it is possible that the observed events of PP elevation were underrepresented.Even though home visits were offered to those too frail to attend the GÅS study central, it is possible that the most frail individuals were underrepresented in this study.Even though PP is an established surrogate for AS, it is dependent of other factors than AS, such as aortic geometry and peak aortic flow, and therefore probably not as precise as measuring carotid-femoral PWV to assess AS 10 .However, since measurement of carotid-femoral PWV to assess AS requires special equipment and is time consuming, carotid-femoral PWV is probably most usable in research, whereas the use of PP as a surrogate for AS is more suitable in the clinical situation due to its accessibility.
In conclusion, the authors suggest that a finding of PP ≥ 80 mmHg in an older subject should raise concern of kidney function and renewed assessment of kidney function by estimating GFR.The authors also believe that the finding of PP ≥ 80 mmHg should raise concern of vascular status, and that evaluation and management of treatable cardiovascular risk factors, such as hypertension, diabetes, and smoking habits, are considered.

Figure 3 .
Figure 3. Kaplan-Meier curve for absence of CKD during follow-up.CKD, chronic kidney disease; PP, pulse pressure.

Table 3 .
Risk of developing CKD during follow-up according to level of pulse pressure elevation at the baseline visit.CKD defined as eGFR < 60 ml/min/1.73m 2 .Statistical method: Univariate and multivariable cox proportional hazard regression models.Covariates: age, sex, diabetes, smoking, BMI, cohort.Significance level: 5% BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; PP, pulse pressure.*PP < 60 mmHg as reference.

Table 4 .
Risk of mortality during follow-up according to level of pulse pressure elevation at the baseline visit.